1. Field of the Invention
This invention relates to conformationally restricted 4-Substituted-2,6-dimethylfuro[2,3-d]pyrimidine compounds and pharmaceutical compositions comprising conformationally restricted 4-Substituted-2,6-dimethylfuro[2,3-d]pyrimidines and pharmaceutically acceptable salts, solvates, or hydrates thereof. Methods of using these compounds and pharmaceutical compositions as multi-targeted receptor tyrosine kinase and microtubule inhibitors and as antitumor agents are provided.
2. Brief Description of the Background Art
Angiogenesis is the “life blood” of tumors and without a new blood supply tumors cannot grow and metastasize.1 During carcinogenesis an angiogenic switch occurs and several angiogenic growth factors stimulate their receptor tyrosine kinases (RTKs) to initiate multiple pro-angiogenic events.2 A therapeutic strategy to inhibit these key angiogenic proteins or their RTKs was envisioned3-5 and multiple inhibitors targeting EGFR, VEGF and/or PDGFR-□ among others are now used clinically. These RTKs are noted to have multi-kinase effects,6 and this appears to be important for optimal activities. Antiangiogenic therapies have proven to be useful clinically in combination with other approaches, and new agents continue to be developed.6 FIG. 1 shows the structures of examples of chemically diverse microtubule depolymerizing agents.
Tubulin binding agents remain some of the most successful cytotoxic cancer chemotherapeutic agents in clinical use (FIG. 1).7 These drugs can be classified as microtubule stabilizers, which stimulate tubulin polymerization, or destabilizers that inhibit tubulin polymerization.8, 9 Drugs that destabilize microtubules were noted to bind to tubulin at two major binding sites, the vinca domain and the colchicine site.7 The vinca alkaloids including vincristine, vinblastine, and vindesine (FIG. 1) bind competitively within the vinca site. These vinca alkaloids have utility in the treatment of both solid and liquid tumors and are used in cancer therapy in both adults and children.7 Structurally diverse natural products and their analogs, including eribulin mesylate and maytansine (FIG. 1) displace the vincas in a noncompetitive manner and they were assumed to bind within the vinca domain and initiate allosteric effects.8,9 Very recent studies by the Steinmtz laboratory now demonstrate that maytansine binds to a distinct microtubule depolymerizer site on β-tubulin that they have designated as the maytansine10 site. Occupancy of this site inhibits tubulin polymerization by preventing the addition of new subunits at the plus ends of the microtubule, a mechanism different from vinca site agents.10 These microtubule targeting agents have clinical utility, since a maytansine derivative is the payload in the antibody drug conjugate T-DM1 (ado-trastuzumab emtansine, Kadcyla®) and eribulin is used in the treatment of breast cancer. The colchicine site is a third non-overlapping microtubule destabilizer binding site on β-tubulin and is located at its interface with α-tubulin. While colchicine is too toxic for use in cancer therapy, a number of colchicine site agents have been evaluated for clinical activity, including 2-methoxyestradiol (2ME2), combretastatin A-4 phosphate (CA-4P) (fosbretastatin), the combretastin CA-1P prodrug (OXi4503) as well as other closely related compounds.7, 11, 12 The interaction of colchicine site agents is intriguing in that some colchicine site agents, notably 2ME2, were developed based on antiangiogenic effects while others including CA-4P, have antivascular effects that initiate rapid destruction of the tumor vasculature. Thus, while these colchicine site agents inhibit tubulin polymerization and cause microtubule depolymerization in cells, there are other mechanistic differences that are not fully understood.
Multidrug resistance remains a major challenge in the curative treatment of cancer, and colchicine site agents have advantages over other microtubule targeting agents because most of them circumvent the P-glycoprotein (Pgp)- and □III tubulin-mediated resistance that have been implicated in limiting the clinical efficacy of other microtubule targeting agents.7, 13 In spite of this no colchicine site agents have yet achieved FDA approval for anticancer therapy. This site has excellent potential for new drug discovery.
Vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and other RTKs are inhibited by small molecules that have considerable utility as targeted cancer chemotherapeutic agents (see FIG. 2, examples of selected RTK inhibitors).14-20 It is well established in the literature that these RTK inhibitors are cytostatic.14, 18, 19 Combination chemotherapy with RTK inhibitors as the antiangiogenic component along with cytotoxic clinically used conventional chemotherapeutic agents are in clinical trials.15, 17, 20 The advantages of combination chemotherapy, particularly with RTK inhibitors, addresses pathway redundancy,17 as well as tumor heterogeneity among other resistance mechanisms, and is beneficial when RTK inhibitors are combined with conventional cancer therapeutics.15, 17, 20 
We sought to combine both RTK inhibitory activities along with cytotoxic activities in single molecules to afford combination chemotherapeutics via single agents.21, 22 In keeping with the principles of combination chemotherapy22, 23 such single entities would act simultaneously at two or more distinct targets and prevent or delay the emergence of resistance, avoid drug-drug interactions, circumvent pharmacokinetic problems and overlapping toxicities that plague combination chemotherapy with two or more separate agents.23 The present invention discloses the structures, design, synthesis and biological activities of novel conformationally restricted bicyclic furo[2,3-d]pyrimidines, which possess potent activities against both tubulin and RTKs.